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Genome wide association study identify novel congenital heart disease risk loci

Commented by the ESC WG on Development, Anatomy & Pathology

Congenital Heart Disease (CHD) affects 7-9 out of 1000 live births [1]. It is a very complex and genetically heterogeneous disorder, which may be caused by genetic insults ranging from single nucleotide variants to large chromosomal aberrations [2]. Identification of genes and genetic variants involved in CHD represent an opportunity to understand the mechanisms which control cardiac development, and when disrupted, cause CHD. However, although significant progress has been made recently [3, 4], a large proportion of the hundreds of genes involved in CHD are currently unknown. In the commented paper this month, a Genome Wide Association Study (GWAS) led by Markus Krane and co-workers from the German Heart Center Munich, identified several novel CHD disease risk loci. In the paper, the authors report the results of a GWAS comprising 4,034 CHD patients and 8,486 healthy controls. Using these large cohorts, they were able to identify novel associations of single nucleotide polymorphisms (SNPs), with genome-wide significance, in chromosomal regions 5q22.2, 20p12.1, 17q21.32 and replicate a previous association to 4p16 [5]. In addition, the authors analyzed the expression of selected genes (MACROD2, GOSR2, WNT3 and MSX1) located within the linkage disequilibrium region of these loci, using a wide range of transcriptomic datasets related to cardiac development and cardiomyogenesis. Although in essence descriptive, these analyses suggested a role for the candidate genes during heart development and thus provided further evidence for CHD association of these candidate genes. In summary, this interesting paper identifies three novel CHD loci and demonstrate the usefulness of GWAS for identification of genetic risk factors in CHD. In the light of these and previous discoveries, additional and larger international GWAS studies on CHD are warranted.


1. van der Linde D, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011;58:2241-2247.
2. Andersen TA et al. Of mice and men: molecular genetics of congenital heart disease. Cell Mol Life Sci 2014;71:1327-1352.
3. Sifrim A et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet 2016;48:1060-1065.
4. Jin SC et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 2017;49:1593-1601.
5. Cordell HJ et al. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16. Nat Genet 2013, 45:822-824.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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